Polyacylated amino diols



Patented Feb. 27, 1951 UNITED STATES PATENT OFFICE POLYACYLATED AMINODIOLS Louis L. Bambas, Grosse Pointe Woods, Mich., as-

signor to Parke, Davis 8; Company, Detroit, Mich a corporation ofMichigan No Drawing. Application January 4, 1950, Serial No. 136,836

0 Acyl NH Acyi R; linemen...

LOG]

where n is 1 or 2 and R is the same or different and representshydrogen, halogen, nitro, lower alkyl or lower alkoxy radicals. The term"acyl as used herein includes saturated and unsaturated lower aliphaticacyl, halogen substituted lower aliphatic acyl, carboxy substitutedlower aliphatic acyl, cyano substituted lower aliphatic acyl, ethersubstituted lower aliphatic acyl, ester substituted lower aliphaticacyl, hydroxy substituted lower aliphatic acyl, benzoyl, substitutedbenzoyl, araliphatic acyl, furoyl, pyridinoyl and the like radicals.

It will be appreciated by those skilled in the art that the products andstarting materials of the invention can exist in structural as well asoptical isomeric forms. The term structura isomer or form as used hereinrefers to the cis or trans, that is, the planar relationship of thepolar groups on the two asymmetric carbon atoms. To differentiatebetween these two possible diastereoisomers we will subsequently referto the cis compounds as the regular (reg.) series or form and to thetrans diastereoisomers as the pseudo (11/) series or form. Such ciscompounds are products wherein the two most highly polar of the groupson the asymmetric carbon atoms lie on the same side of the plane of thetwo carbon atoms. Conversely, the trans or pseudo compounds are thosewherein the two most highly polar groups lie on opposite sides of theplane of the two carbon atoms.

Both the regular and pseudo forms exists as racemates of the opticallyactive dextro (d) and levo (1) rotatory isomers as well 'as in the formof the individual or separated dextro (d) and levo (l) isomers.

Because of the dlfficulty of representing these structural difierencesin graphic formulae the customary structural formulae will be used inboth the specification and claims and a notation placed below or to theside of the formula to designate the particular structural and opticalconfiguration of the compound. Where the formula represents theunresolved mixture of the structural and optical isomers the notationunresolved will be used. However, it should be expressly understood thatwhere no notation appears with a structural formula the formula is to beinterpreted in its generic sense. that is. as representing the (1) (d)(1) -reg. or (d) -reg. isomers in separated form as well as the (d1) 4'or the (d1) -reg. optical racemates or the total unresolved mixture ofstructural and optical isomers. Such a formula does not merely representthe unresolved mixture of isomers.

In accordance with the invention, the polyacylated amino diols of theabove general formula are produced by acylating the compounds of theformula,

on NHR1 lemme...

LQOJ

where R1 and R: are the same or different and represent hydrogen or acylradicals and R and n have the same significance as given above. Asacylating agents either acyl halides or acyl anhydrides can be used.These acylating agents which are preferably employed under substantiallyanhydrous conditions can be used alone or in conjunction withalkalinecatalysts such as alkali or alkaline earth metal hydroxides,carbonates and oxides, tertiary amines and the like. Some specificexamples of suitable alkaline catalysts are sodium hydroxide, potassiumhydroxide, lithium hydroxide, barium hydroxide, potassium carbonate,calcium oxide, pyridine, dimethylaniline, N-ethyl piperidine, N-ethylmorpholine,

' quinoline, triethylamine and the like. In general,

when no alkaline catalyst is employed, the reactants must be heatedtogether in order to bring about the reaction in a reasonable time. Inmost instances a heating period of several hours sufflees. When analkaline catalyst is employed, heating is usually not necessary as thereaction proceeds with suificient rapidity at moderate temperatures,that is, below about 50 C. In some instances, however. where the acylhalide or anhydride is not particularly reactive, it is advantageous tocarry out the reaction at a temperature above about 50 C.

This acylation process can also be carried out in an aqueous medium.This is most conveniently accomplished by using a two-phase reactionmixture, that is, one consisting of water and a water-immiscible organicsolvent, such as etl' l acetate, ether chloroform and ethylene dichride. In such a case it is preferable to carry out the reaction at about25 C. or below and to employ a weakly alkaline material in conjunctionwith the acyl halide or anhydride. Some examples of the weakly alkalinecatalysts which can be used are calcium carbonate, magnesium carbonate,barium carbonate and the like.

As pointed out above, the amino diols of the invention and theiracylated derivatives can exist in structural as well as optical isomericforms. Where a particular optical isomeric form or optical racemate ofone of the two structural forms of these products is desired, it isnecessary to separate the unresolved amino diol or acylated amino diolinto its two component structural isomers. This is accomplished quitereadily and completely by utilization of the differences in solubilityof the two forms in water, organic solvents or in water-organic solventmixtures. Some of the organic solvents which can be used in thisfractional crystallization or solubilization are lower aliphaticalcohols, acetone, chloroform, ethyl acetate and the like. In somecases, the solvent solubility differential of the two forms is not greatenough to afford a clean-cut separation of the two structural isomersand in these cases it is preferable to convert the isomer mixture of thefree amino diol or acylated amino diol into another acylated derivativeof the amino diol whose structural isomers differ more markedly in theirsolubility characteristics. The structural isomers of this new acylatedamino diol can then be separated by fractional crystallization and theappropriate structural form of the product so obtained converted eitherby acylation or hydrolysis to the desired structural form of the freeamino diol or acylated amino diol.

Where a particular optical isomer of the amino diol or acylatedderivative thereof is desired the corresponding individual regular orpseudo structural form of the 1-(4-biphenylyl) -2-aminopropane-1,3-dio1is resolved into its optical isomers via an optically active acidaddition salt. This resolution which must be carried out on the freeamino diol is performed by forming an acid addition salt of the racemicamine with an optically active acid such as (d) -tartaric, (D-tartaric,(d) -mandelic, (l)-mandelic, (d)- bromcamphor sulfonic, (l)-bromcamphors fonic, (d) -camphor sulfonic, and (l)-camphor sulfonic acids,separating the two isomeric salts by recrystallization from a solventsuch as a lower aliphatic alcohol or mixtures of the same with water orother organic solvents and then regenerating the individual opticalisomers from the separated optically active acid addition salts byneutralizing each one separately. When carrying out this resolution itis desirable, but not absolutely necessary, to choose the form of theoptically active acid so that the-desired optical isomer will separatefrom the crystallization solution first.

The polyacylated amino diol compounds of the invention are valuableintermediates for the preparation of other organic compounds. They areof particular value as intermediates for the preparation of organiccompounds possessing antibiotic activity.

The invention is illustrated by the following examples: Example 1 3.2 g.of (dl)-/-1-(4'-nitro-4-biphenylyl)-2- aminopropane-1,3-diol is added toa mixture composed of 6 cc. of acetic anhydride and 6 cc. of drypyridine and the resulting mixture is heated at 100 C. for aboutone-half hour. The reaction mixture is evaporated to dryness in vacuoand the residue recrystallized from methanol to obtain the desired (dl)--1-(4'-nitro-4- 4 biphenylyl) 2 acet'amido 1,3 dlacetoxypropane of theformula,

(dl)-,9 Form Example 2 (dl)-1P Form Example 3 5.0 g. of (dl)-reg.-1-(2'-chloro-3-biphenylyl)- 2 phenylacetamido 3cyanoacetoxypropanel-ol is added to 5 cc. of dry pyridine and thesolution cooled to 03 C. 2 g. of benzoyl chloride is added and thesolution is allowed to stand for one hour. The reaction mixture isdiluted with water, extracted with ethyl acetate and the extract washedsuccessively with dilute hydrochloric acid, sodium bicarbonate solutionand water. The ethyl acetate extract is dried and the ethyl acetatedistilled in vacuo to obtain the crystalline (dl) reg. 1 (2' chloro 3biphenylyl) 2 phenylacetamido 3 cyanoacetoxy 1 benzoyloxypropane of theformula,

I NH- C-CHI-O H- H-CHrO-C-CHzCN (an-neg. form Example 4 6.3 g. of (d)-reg.-1-(2',4'-dimethoxy-4-biphenylyl) 2 nicotinamidopropane 1,3 diol isheated at C. for one hour with a mixture consisting of 20 cc. of drypyridine and 10 cc. of methoxyacetic anhydride. The reaction mixture isevaporated to dryness in vacuo, the residue taken up in water, extractedwith ethyl acetate and the ethyl acetate layer washed with dilutehydrochloric acid, dilute sodium bicarbonate solution, and water. Theextract is dried, the ethyl acetate distilled, and the residuerecrystallized from ethanol. The product thus obtained is (d)-reg.-1-(2,4'-dimethoxy-4-biphenylyl) 2 nicotinamidopropane 1,3 bis-(methoxyacetoxy) propane of the formula,

0-i-CHIO C NIL-EU Example 5 are treated with 8 g. of succinic anhydrideand 2 f ((11) the mixture heated on a steam bath for one hour.lactamidopropane-l,3-diol or the corresponding The Solution is cooled,diluted with 200 of 2 acetoxylactamido derivative is heated at 85 C. Nhy oc o c ac d and extracted w t ethyl with a mixture consisting of cc.of dry pyridine acetate. The ethyl acetate is washed with acidand 6 cc.of acetic anhydride for one and onem water (pH 4 and finally t 120 9fhalf hours The liquid is then evapmted in 0.5 N sodium bicarbonatesolution. The pH of vacuo, the gummy residue taken up in ether andwashed successively with dilute hydrochloric acid, the p g Wash broughtto 2 wlth 2 hydro sodium bicarbonate solution, and water. The 10 chloricacid and the crystalline precipitate colether extract is dried, theether evaporated and f Thls product is (11) the residue recrystallizedfrom ether-petroleum D y yD- -Su00inaid0 1,3 bis(succin0y ether mixtureto obtain the pure (d1) --1-(2- oxy) propane of the formula.

(dB-Beg. form ethyl 4 biphenylyl) 2 acetoxylactamido- Example 91,3-diacetoxypropane of the formula, v

0 4.2 g. of (d) -ip-1-(2-methoxy-4-biphenylyl)- 0 o g r 2-343dimethylacrylamido 3 acetoxyacetoxy- H g propane-l-ol in 10 cc. of drypyridine is heated 11-4338 with 4 g. of furoic anhydride and thesolution CH H-CHaO-G-CH; heated for two hours on a steam bath. The re-'action miture is diluted with water, extracted 0,115 with ethyl acetateand the extract is washed D-i Form successively with dilute hydrochloricacid, sodium g z 6 bicarbonate solution and water. The ethyl aceof tateextract is dried, the ethyl acetate distilled, dichloroacetamido 3dichloroacetoxypropaneand the res1 due crystaulz ed from ethyl acetate-1-ol is added to a mixture composed of 3 cc. of mthan1m1xtur to obtamthe deSIII'ed -5 dichloroacetic anhydride and 3 cc. of dry py idine (2methoxy'4'blphenylyl) -f fi' and the resulting mixture is heated at 100C. amldo 3 acetoxyacetoxy 1 fumyloxypropane for one-half hour. Thereaction mixture is of the formulaevaporated to dryness in vacuo and theresidue recrystallized from ethanol to obtain the desired 40 (d1) l 1(4' nitro 4 biphenylyl) 2 di- 0 chloroacetamido 1,3bis(dichloroacetoxy)pro- J; pane. This product has the formula, 0

O O 0 CH: (ii-iL-CHC]; NH-l-CHCI: NH-E CH=C/ NOz- -cH H-CHiO-C-CHCI; loH,

t H- H-CHSO'C-CHQOC CHI an-1p Form a 8 Example 7 0H; 1.7 g. of(l)-i//-1-(3'-methyl-4-biphenylyl)-2- H Form aminopropane-l,3-diol isadded to 10 cc. of dry pyridine and the solution cooled to 0 C. 5 g, ofp-toluyl chloride is added and the solution al- Example 10 lowed tostand for two hours. The reaction mixture is diluted with water,extracted with ethyl 8 g. of (l)-reg.-1-(4'-bromo-4-biphenylyl)-2-acetate, and the extract is washed successively bromoacetamido3-propionyloxypropane-l-ol in with dilute hydrochloric acid, sodiumbicarbonate 10 cc. of pyridine is treated with 5 g. of nicotinoylsolution and water. The ethyl acetate extract chloride at 0 C. for onehour. The reaction mixis dried and the ethyl acetate distilled in vacuoture is diluted with water, extracted with ethyl to obtain thecrystalline (l)-\, /-1-(3'-methyl-4- acetate and the ethyl acetateextract is washed biphenylyl) -2-p-toluylamido 1,3bis(p-toluylsuccessively with dilute hydrochloric acid, sodium oxy)propane of the formula, bicarbonate solution and water. The ethyl ace-Oi CH. NLE CH. LH L CH.O O= OH.

JJ a

(Iil Form Example 8 tate layer is dried and the ethyl acetate distilled5 of in vacuo to obtain the desired (1) -reg.-1-(4'-aminopropane-LZ-diol in 10 cc. of dry pyridinebromo-l-biphenylyl)-2-bromoacetamido-3-propionyloxy-i-niootinoyloxypropanc or the for-- mula,

0 NIL-EH13! Br-O-O- n-cn-cmo-z-cm-cm (1)420. form Example 11 g. oi. (d1)--1-(4-biphenylyl) -2-acetamido-3- acetowpropane-l-ol is treated with 5g. of acetic anhydride in ml. of dry pyridine. The mixture is heated at60 C. for two hours and is then diluted with water. extracted with ethylacetate and the ethyl acetate extract washed successively with dilutehydrochloric acid, sodium bicarbonate solution, and water. The organiclayer is dried and the ethyl acetate distilled in vacuo to obtain (d1)b-l-(i-biphenylyl) -2-acetamido-1,3-diacetoxypropane oi the formula.

0 o o-L-crn NH-il't-CH: O-O-on H-cmo-c-cm [6114 Ion! 0 NBAcylhenmethylene OO- -cH-cmon Biphenylyl acylamido diols lparthl scylationOH NHAcyl Example 12 10 g. of (d1)--1-(4-diphenylyl)-2-dichloroacetamidopropane-L3-dio1 is added to 20 cc.of acetic anhydride and 25 cc. of dry pyridine. The mixture is heated atC. for two hours and is then evaporated in vacuo. The residue is treatedwith water and the solid (dll-w-l-G- diphenylyl)-2-dlchloroacetamido-l,3 diacetoxypropane is collected andrecrystallized from ethyl acetate. The formula of this product is,

O 0 O-E-CH; NH-El-OHCI:

O-O-dn n-cmo-c-cm (dD-V Form In the foregoing examples we have employedas starting materials products having the formula,

OH NHR:

R- I- H-lH-CILORI TOQJ where R and n have the same significance as givenabove and R1 and R: are the same or different and represent hydrogen oracyl radicals. These starting materials can be prepared in a number ofdifferent ways. One of the general methods which can be used to preparethe compounds of the type depicted above is that represented by thefollowing diagram.

QOcE-eH-cmo Acyl Biphonylyl acylunido acyhxy alcohols The preparation ofthe unresolved starting materials has not been shown in the abovediagram but these products may be prepared by the indicated processes byomitting the steps of separating the structural and optical isomers. Thefollowing examples serve to illustrate the application of this method tothe preparation of some of the specific starting materials used in theforegoing examples.

(a) 75 g. of hexamethylenetetramine dissolved in chloroform is added to125 g. of 4-biphenylyl bromomethyl ketone and the mixture allowed tostand at room temperature for about three hours. The 4-biphenylylbromomethyl ketone-hexamethylenetetramine complex is collected, washedwith a little chloroform and dried. The formula of this product is,

o O-O-iz-cmwml-Nm:

(b) 175 g. of the 4-biphenylyl bromomethyl ketone hexamethylenetetraminecomplex is added to 200 cc. of concentrated hydrochloric acid in 1 literof absolute alcohol and the mixture stirred overnight. The insolublehydrochloride salt of 4-biphenylyl aminomethyl ketone is collected byfiltration, washed with a small amount of cold water and dried at roomtemperature. The formula of this product is,

tion has been completed the solution is diluted with water and the4-biphenylyl acetamidomethyl ketone which separates collected andrecrystallized from methanol; M. P. 154-5 C. The formula of thiscompound is,

O 0 GD" i C-CHaNH- -CH;

((1) 58 g. of 4-biphenylyl acetamidomethyl ketone is mixed with 300 cc.of methanol and 75 cc. of 40% neutral formalin. 2 g. of sodiumbicarbonate is added and the mixture stirred at room temperature forabout an hour during which time the desired solid product separates. Theinsoluble 4-biphenyly1 a-acetamido-fi-hydroxyethyl ketone of formula,

0 O NH--CHI II I is collected and purified by recrystallization fromethyl acetate; M. P. 166-6 C.

(e) g. of 4-biphenylyl-u-acetamido-,8-hydroxyethyl ketone is mixed with75 g. of aluminum isopropylate and 1 liter of isopropanol and themixture heated under reflux for five hours. During the refluxing periodthe acetone which is formed is distilled off and a stream of nitrogen ispassed through the solution. The isopropanol is distilled from thereaction mixture under reduced pressure and the residue treated withabout 1 liter of water. The mixture is heated to boiling to insurecomplete precipitation of the aluminum hydroxide, filtered while hot andthe filtrate allowed to cool. The (d1) --1-(4- biphenylyl) 2 acetamidopropane 1,3 diol which separates from the cool solution is collected byfiltration and purified by recrystallization from 40% ethanol; M. P.190-1 C. The formula of this product is,

were...

If desired, the corresponding (d1) -reg. isomer may be recovered fromthe aqueous filtrates.

(f) 12 g. of (d1) -1p-1-(4-biphenylyl) -2-acetamidopropane-1,3-diol isheated with 400 cc. of 5% hydrochloric acid for twelve hours. Thereaction mixture is cooled and the hydrochloride salt of (d1) l/-1-(i-biphenylyl) -2-aminopropane- 1,3-diol which separates collected andwashed with a small amount of water and the solution treated with anexcess of ammonium hydroxide.

The (dl) 1p 1 (4 biphenylyl) 2 aminopropane-l,3-diol free base whichseparates is collected and purified by recrystallization from water; M.P. 149-50" C. The formula of this product is,

011 NH: 3 ll1iH-CH10H (GD-x11 Form (g) 3 g. of (d1) -/-1-(4-biphenylyl)-2-aminopropane-1,3-diol is dissolved in a minimum amount of watercontaining a small amount of methanol and the resulting solution treatedwith an aqueous solution containing an equivalent amount of (d)-tartaric acid. The solution is evaporated to dryness in vacuo and theresidue fractionally crystallized from a minimum amount of hot methanol.The first isomer to separate from the solution in crystalline form isthe (d) tartaric acid salt of (l)- l'-l-(4-biphenylyl)-2-aminopropane-L3-diol. The (d) tartaric acid salt of (d)-i//-1-(4-biphenylyl) -2-aminopropane- 1,3-diol is recovered from thefiltrates after removal of the salt of the (l) -isomer.

The (d)-tartaric acid salt of (l) -\//-1-(4-biphenylyl) 2aminopropane-1,3-diol obtained above is dissolved in water, the solutionmade alkaline to pH 9 with sodium hydroxide solution and theprecipitated (l)--1-(4-biphenylyl)-2- aminopropane-1,3-diol free basecollected. The formula of this product is,

OH NH,

(1)4 Form By decomposing the (d) -tartaric acid salt of (d) -\//-1-(l-biphenylyl).-2-aminopropane-1,3-diol in the same manner as describedabove for the (l)-isomer, one obtains the free base of (d)-1//-1-(l-biphenylyl)-2-aminopropane-1,3-diol. In an analogous manner the (d1)--l-(4-biphenylyl)- 2-amin0propane-1,3-diol may be resolved into itsisomeric forms via the (d) -camphor sulfonic acid salt. This isaccomplished by reacting the optically active acid with the racemic basein butanol or isopropanol and separating the isomers byrecrystallization from n-butanol or isopr0- 1 panel. The salt of the (l)-isomer separates from 11 to obtain the desired (1)--1-(4-bipheny1yl)-2- dichloroacetamidopropane- 1,3-d1ol or formula,

O-OcH-oIL-QILOH EZ L CH.O E CB.

(dl)-w Form some or the subject matter disclosed but not claimed hereinis described and claimed in my copending applications Serial Nos.136,831, 136,832, 136,833, 136,834, 136,835, 136,837 and 136,838, allfiled January 4, 1950, as continuations-in-part of my application SerialNo. 83,778, now Patent No. 2,516,098.

12 What I claim is: 1. 4 compound of formula,

0 L011 NHLcyl where n is one of the integers 1 and 2 and R is a memberof the class consisting of hydrogen, halogen, -N0-.-, lower alkyl andlower alkoxy radicals.

2. A compound of formula.

0 Acyl NH Aclyl 3. (dl) ,0 1 (i-biphenylyl) 2 acetamido-1,3-diacetoxypropane.

4. (dl)-ip-1-(4-bipheny1yl) -2-dichloroacetamido-1,3-diacetoxypropane.

5. A compound or Iormula,

0 Any] NH Acyl 6. (dl) t1-(4-nitro-4-biphenyly1)-2-acetamido-1,3-diacetoxypropane.

7. (dl) 4/ 1 (4' nitro-4-biphenylyl)-2-di-,chloroacetamido-1,3-diacetoxypropane.

LOUIS L. BAMBAS.

No references cited.

1. A COMPOUND OF FORMULA